Catechol-O-Methyltransferase Valine¹⁵⁸Methionine Genotype and Resting Regional Cerebral Blood Flow in Medication-Free Patients with Schizophrenia

Background: A valine¹⁵⁸methionine (val¹⁵⁸met) polymorphism in catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized. Methods: Twenty-five medication-free patients (28 ± 6 years; 19 male patients) and 47 healthy individuals (29 ± 8 years; 33 male individuals) were genotyped for the COMT val¹⁵⁸met polymorphism and underwent two 60-second radiolabeled water ([¹⁵O]H₂O) regional cerebral blood flow (rCBF) positron emission tomography scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate. Results: In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow in the right dorsolateral PFC, right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus. Conclusions: In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity.